Perspectives on using a multiplex human kidney safety biomarker panel to detect cisplatin-induced tubular toxicity in male and female Cynomolgus monkeys

摘要

Abstract Multiplex biomarker panel assays would enable early de-risking of discovery compound related kidney safety liabilities. The objective of this study was to evaluate the usefulness of the Myriad RBM Human KidneyMAP (Multi-Analyte Profile)? v.1.0 panel to detect experimental nephrotoxicity in Cynomolgus monkeys following a single intravenous administration of cisplatin (2.5mg/kg). Urine samples were collected at baseline on day ?2; at approximately 4hr post-dose on day 1; and on days 4, 9, 15 and/or 20. Blood samples were collected at predose on day ?2; at 4hr post-dose on day 1; and on days 2, 5, 10 and/or 21. Changes in toxicokinetic and biochemistry parameters in plasma, qualitative/quantitative urinalysis parameters, and urinary kidney safety biomarkers were assessed. Kidney tissues were collected on days 2, 5, 10 and 21 for routine microscopy. Cisplatin-induced tubular alterations were characterized by acute and progressive cortical tubular degeneration/necrosis, regeneration, tubular dilation and proteinaceous cast in the absence of statistically significant changes in traditional plasma biochemistry and urinalysis parameters. When normalized to urinary creatinine, cisplatin-induced significant increases in urinary levels of kidney injury molecule 1 (females on day 4), increases in calbindin D28k (males and females on day 4), decreases in Tamm-Horsfall glycoprotein (males on days 1, 4 and 9), and increases in clusterin (females and males on days 15 and 20, respectively), when compared to concurrent controls. This study revealed the usefulness of the Human KidneyMAP? multiplex panel when measuring changes in urine-based biomarkers to reliably detect cisplatin-induced acute/progressive cortical tubular injury in male and female Cynomolgus monkeys. Highlights ? Cisplatin-induced cortical tubular injury was identified in Cynomolgus monkeys. ? Plasma creatinine and urea nitrogen did not indicate nephrotoxicity. ? Early increases in urinary calbindin and KIM-1 indicated acute tubular injury. ? Rises in urinary clusterin indicated progressive cortical tubular injury. ? Decreased urinary THP indicated progressive tubular injury.